JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Growth of self-perceived clinical competence in postgraduate training for general practice and its relation to potentially influencing factors.

OBJECTIVE: To examine the increase in self-perceived clinical competence during a three-year postgraduate training in general practice and to explore the relation between the growth of self-perceived competence and several background variables. DESIGN: Cohort, 1995-1998. SETTING: Three-year Postgraduate Training for General practice in the Netherlands PARTICIPANTS: All Dutch trainees who followed postgraduate training from September 1995 to September 1998 (N=191). INTERVENTION: We asked the trainees at the start and at the end of their postgraduate training to complete a questionnaire, which assessed their self-perceived knowledge, clinical skills and consultations skills. We collected information about potentially influencing background variables. Amongst these were variables such as: age, gender, prior medical experience, the effort someone has spent upon her/his education, insight in weak and strong areas of clinical competence and knowledge and skills levels. MAIN OUTCOME MEASURE: Self-perceived competence. RESULTS: A total of 127 trainees completed both questionnaires (190 at the first administration and 128 at the second one). We found statistically significant growth of self-perceived clinical competence. Self-perceived consultation skills increased more than self-perceived knowledge and clinical skills. The afore mentioned background variables did not relate in any way with the growth of self-perceived clinical competence. CONCLUSION: This study shows that a 3-year postgraduate training in general practice enhances self-perceived clinical competence. However, we still do not know how to explain this improvement. Further study into the theoretical concept of self-assessment in medical education and into the factors contributing to the feeling of being competent, is required.

Acquisition of communication skills in postgraduate training for general practice.

PURPOSE: The evidence suggests that a longitudinal training of communication skills embedded in a rich clinical context is most effective. In this study we evaluated the acquisition of communication skills under such conditions. METHODS: In a longitudinal design the communication skills of a randomly selected sample of 25 trainees of a three-year postgraduate training programme for general practice were assessed at the start and at the end of training. Eight videotaped real life consultations were rated per measurement and per trainee, using the MAAS-Global scoring list. The results were compared with each other and with those of a reference group of 94 experienced GPs. RESULTS: The mean score of the MAAS-Global was slightly increased at the end of training (2.4) compared with the start (2.2). No significant difference was found between the final results of the trainees and the reference group. According to the criteria of the rating scale the performance of both trainees and GPs was unsatisfactory. CONCLUSION: The results of this study indicate that communication skills do not improve in a three-year postgraduate training comprising both a rich clinical context and a longitudinal training of communication skills, and that an unsatisfactory level still exists at the end of training. Moreover, GPs do not acquire communication skills during independent practice as they perform comparably to the trainees. Further research into the measurement of communication skills, the teaching procedures, the role of the GP-trainer as a model and the influence of rotations through hospitals and the like, is required.

Predictive validity of a written knowledge test of skills for an OSCE in postgraduate training for general practice.

PURPOSE: To examine the validity of a written knowledge test of skills for performance on an OSCE in postgraduate training for general practice. METHODS: A randomly-selected sample of 47 trainees in general practice took a knowledge test of skills, a general knowledge test and an OSCE. The OSCE included technical stations and stations including complete patient encounters. Each station was checklist rated and global rated. RESULTS: The knowledge test of skills was better correlated to the OSCE than the general knowledge test. Technical stations were better correlated to the knowledge test of skills than stations including complete patient encounters. For the technical stations the rating system had no influence on the correlation. For the stations including complete patient encounters the checklist rating correlated better to the knowledge test of skills than the global rating. CONCLUSION: The results of this study support the predictive validity of the knowledge test of skills. In postgraduate training for general practice a written knowledge test of skills can be used as an instrument to estimate the level of clinical skills, especially for group evaluation, such as in studies examining the efficacy of a training programme or as a screening instrument for deciding about courses to be offered. This estimation is more accurate when the content of the test matches the skills under study. However, written testing of skills cannot replace direct observation of performance of skills.